Drug delivery devices for setting and dispensing a single or multiple doses of a liquid medicament are as such well-known in the art. Generally, such devices have substantially a similar purpose as that of an ordinary syringe.
Drug delivery devices, in particular pen-type injectors have to meet a number of user-specific requirements. For instance, with patient's suffering chronic diseases, such like diabetes, the patient may be physically infirm and may also have impaired vision. Suitable drug delivery devices especially intended for home medication therefore need to be robust in construction and should be easy to use. Furthermore, manipulation and general handling of the device and its components should be intelligible and easy understandable. Moreover, a dose setting as well as a dose dispensing procedure must be easy to operate and has to be unambiguous.
Typically, such devices comprise a housing, adapted to receive a cartridge at least partially filled with the medicament to be dispensed. The device further comprises a drive mechanism, typically having a displaceable piston rod which is adapted to operably engage with a piston of the cartridge. By means of the drive mechanism and its piston rod, the piston of the cartridge is displaceable in a distal or dispensing direction and may therefore expel a predefined amount of the medicament via a piercing assembly, which is to be releasably coupled with a distal end section of the housing of the drug delivery device.
The medicament to be dispensed by the drug delivery device is provided and contained in a multi-dose cartridge. Such cartridges typically comprise a vitreous barrel sealed in distal direction by means of a pierceable seal and being further sealed in proximal direction by the piston. With reusable drug delivery devices an empty cartridge can be replaced by a new one. In contrast to that, drug delivery devices of disposable type are to be entirely discarded when the medicament in the cartridge has been dispensed or used-up.
With such multi-dose drug delivery devices at least a last dose limiting mechanism is required to inhibit setting of a dose exceeding the amount of medicament which is left in the cartridge. This is to avoid a potentially dangerous situation for the user believing that a set dose is entirely injected.
There already exist some drug delivery devices with such end-of-content mechanisms or last dose mechanisms.
Document WO 2009/132778 A1 for instance discloses a dose limiting member designed for axial movement in a proximal direction with respect to the piston rod during dose setting. The dose limiting member comprises a first stop element and the piston rod comprises a second stop element. First and second stop elements stop an axial movement of the dose limiting member in the proximal direction with respect to the piston rod when the first and second stop elements catch, thereby limiting a movement of the dose setting member for increasing a set dose of medication to be delivered. There, the dose limiting member and the piston rod only interact directly, when the first and second stop elements catch.
Apart from such a last dose limiting mechanism it may be also required to provide a single dose limiting mechanism by way of which the maximum size of a dose to be set and dispensed can be limited to a predefined maximum.
It is therefore an object of the present invention to avoid disadvantages of known drug delivery devices and to provide a single dose limiting mechanism as well as a last dose limiting mechanism.
It is another object of the present invention to provide a drive mechanism for a drug delivery device for setting and dispensing of a dose of a medicament typically provided in a cartridge, wherein the drive mechanism is equipped with a single dose limiting mechanism and with a last dose limiting mechanism.
It is a further object to provide a drug delivery device comprising such a drive mechanism and comprising a cartridge sealed with a piston to become operably engaged with a piston rod of such drive mechanism.
In a first aspect a drive mechanism for a drug delivery device is provided for dispensing of a dose of a medicament. The drive mechanism comprises an elongated housing extending in an axial direction. Preferably, the housing is of substantially tubular or cylindrical shape that allows gripping and operating of the drive mechanism or of the entire drug delivery device by one hand of a user.
The drive mechanism further comprises a piston rod to operably engage with a piston of a cartridge containing the medicament to be dispensed by the drive mechanism. The cartridge comprises a piston, which, by means of a displacement in axial distal direction, serves to expel an amount of the medicament from the cartridge that corresponds to the axial displacement of the piston. The piston typically seals the cartridge in axial proximal direction. The piston rod serves to displace the piston of the cartridge in an axial distal direction. The piston rod is therefore operable to apply distally directed thrust or pressure to the piston of the cartridge for displacing the same in distal direction for a predetermined distance that corresponds to a respective amount of the medicament to be dispensed.
The drive mechanism further comprises at least one drive sleeve which is rotatably supported in the housing and which is operably releasable from the piston rod for setting of a dose. Hence, during a dose setting procedure, the piston rod remains substantially stationary with respect to the housing while the drive sleeve, operably disconnected and released from the piston rod, is rotatable relative to the housing and hence relative to the piston rod.
However, for dispensing of the set dose, the drive sleeve is operably engageable with the piston rod. In a respective dose dispensing mode, piston rod and drive sleeve are operably engaged for that the drive sleeve may exert a driving force or driving momentum to the piston rod for driving the same in distal direction to displace the piston of the cartridge accordingly.
The drive mechanism further comprises a dose limiting member engaged with the drive sleeve and engaged with the piston rod in such a way, that the dose limiting member is displaced in axial direction relative to the drive sleeve and/or relative to to the piston rod when the drive sleeve rotates relative to the piston rod during a dose setting procedure. The dose limiting member is provided as a separate component of the drive mechanism and is directly engaged with the drive sleeve as well as with the piston rod.
The drive mechanism further comprises at least one stop for limiting the axial displacement of the dose limiting member during the dose setting procedure. The at least one stop typically comprises a stop face to engage or to abut with the dose limiting member when a dose limiting configuration of the drive mechanism has been reached during a dose setting procedure. When the at least one stop and the dose limiting member mutually engage, the at least one stop serves to impede or to block further displacement of the drive sleeve relative to the piston rod.
Since the dose limiting member is directly engaged with both, the drive sleeve and with the piston rod, the mutual engagement of the at least one stop with the dose limiting member also serves to impede a further displacement of the drive sleeve relative to the housing. By impeding or blocking the displacement of the drive sleeve relative to the piston rod and/or relative to the housing, a dose setting procedure can be interrupted and blocked.
By means of the separate dose limiting member a single dose limiting mechanism can be implemented allowing to limit or to confine the maximum amount of the medicament of a single dose during a dose setting procedure. The maximum size of a dose is correlated to the mutual engagement of the dose limiting member with the drive sleeve and/or with the piston rod. Moreover, the size of the maximum dose to be limited by the single dose limiting mechanism can be further varied and specified by the geometry of the dose limiting member as well as by the geometry, position and orientation of the at least one stop.
Moreover, interchanging of the dose limiting member by a dose limiting member of different size or geometry allows to modify the size of the maximum dose to be set and to be dispensed by the drive mechanism and by the respective drug delivery device. In this way, the drive mechanism can be in principle adapted and configured to different medication requirements. In case of e.g. a drug delivery device for injecting insulin from a cartridge, the dose limiting member may be configured to set a maximum dose of 120 international units (I.U.). For other drug delivery devices or for a different medicament or medicament type, a maximum dose of e.g. 80 I.U. or 50 I.U. may be required.
Variable sizes of maximum doses may be easily implemented with the drive mechanism by replacing the dose limiting member with a differently configured dose limiting member. For instance, respective dose limiting members may differ with regard to their axial extension and size.
In a further embodiment, the drive sleeve encloses the circumference of the piston rod at least in an axial section. Typically, the drive sleeve is open towards the distal direction and receives or accommodates a proximal portion of the piston rod, at least in an initial device configuration. The piston rod and the surrounding drive sleeve are typically arranged concentrically. Hence, the piston rod is located in the radial centre of the drive sleeve and is co-aligned with the drive sleeve in axial direction. While the drive sleeve is rotatably supported in the housing it may only experience a limited axial displacement, e.g. for switching between a dose setting mode and a dose dispensing mode of the drive mechanism. In contrast to that, the piston rod advances in distal direction with every consecutive dose dispensing procedure. With repeated dose dispensing procedures the piston rod may therefore protrude more and more in axial direction from the drive sleeve.
The dose limiting member is further arranged radially between the drive sleeve and the piston rod. Due to the location between the drive sleeve and the piston rod, the dose limiting member is engaged with an inside facing surface of the drive sleeve and with an outside facing surface of the piston rod. By arranging the dose limiting member radially between the drive sleeve and the piston rod, the single dose limiting mechanism can be provided substantially inside the drive sleeve, which allows for a rather space-saving arrangement of the single dose limiting mechanism. In this way, the outer circumference of the drive sleeve does not have to provide any means for a single dose limiting mechanism. As a consequence, the drive sleeve can be designed in a rather compact way.
According to a further embodiment, the dose limiting member is threadedly engaged with the drive sleeve. For this purpose, the dose limiting member comprises an outer thread to engage with a correspondingly designed inner thread of the drive sleeve. By means of the threaded engagement of dose limiting member and drive sleeve, a rotation of the drive sleeve relative to the piston rod can be transferred to an axial displacement of the dose limiting member, given that the dose limiting member is hindered to rotate with the drive sleeve.
In a further preferred embodiment, the dose limiting member is rotatably fixed to the piston rod but it is axially slideably engaged with the piston rod. In other words the dose limiting member is splined to the piston rod. Hence, the dose limiting member cannot rotate relative to the piston rod but is free to slide along the piston rod in axial direction. Since the dose limiting member is axially slideably engaged with the piston rod it may slide along the piston rod in axial direction during a relative rotation of drive sleeve and piston rod.
Preferably, the dose limiting member is displaceable in proximal direction during a dose setting procedure and is operable to return to an initial position in distal direction during a dose dispensing procedure.
Since the dose limiting member is splined to the piston rod and since the dose limiting member is threadedly engaged with the drive sleeve, it is engaged with the drive sleeve and with the piston rod in such a way, that it is displaced in axial direction relative to the drive sleeve when the drive sleeve rotates relative to the piston rod during a dose setting procedure.
According to an alternative embodiment it is also conceivable that the dose limiting member is rotatably fixed to the drive sleeve but is axially slideably engaged with the drive sleeve. At the same time, the dose limiting member is threadedly engaged with the piston rod. Also in this configuration, the dose limiting member is engaged with the drive sleeve and with the piston rod in such a way, that it is displaced in axial direction relative to the drive sleeve when the drive sleeve rotates relative to the piston rod during a dose setting procedure.
In this alternative embodiment, the dose limiting member is splined with the drive sleeve and is therefore rotatably coupled with the drive sleeve. A rotation of the drive sleeve is therefore unalteredly transferable to a respective rotation of the dose limiting member. Due to the threaded engagement of the dose limiting member and the piston rod, the dose limiting member may preferably displace relative the piston rod in proximal direction during a dose setting procedure initiated by the drive sleeve.
The alternative embodiment, wherein the dose limiting member is splined with the drive sleeve and wherein the dose limiting member is threadedly engaged with the piston rod provides an alternative approach of a mutual engagement of dose limiting member, drive sleeve and piston rod for displacing the dose limiting member relative to the drive sleeve and/or relative to the piston rod in axial, preferably in proximal direction during a dose setting procedure.
In another embodiment, wherein the dose limiting member is threadedly engaged with the drive sleeve and wherein the dose limiting member is rotatably fixed to the piston rod, the piston rod comprises an axially elongated groove or notch to receive a radially inwardly extending gliding portion of the dose limiting member. The gliding portion of the dose limiting member provides a kind of a tappet mating and engaging with the geometry of the piston rod's groove. The gliding portion therefore serves to rotatably fix the dose limiting member to the piston rod. Moreover, it provides a controlled axially directed sliding displacement of the dose limiting member relative to the piston rod.
Preferably, the piston rod comprises an outer thread to engage with the housing or with another component of the drive mechanism, e.g. a drive nut of the drive mechanism. In such embodiments, the elongated groove of the piston rod intersects and interrupts the external thread of the piston rod.
Moreover, by the elongated groove, the piston rod can be in principle splined to the housing of the drive mechanism and/or of the drug delivery device. In this way, the axially elongated groove of the piston rod provides a double function. When arranged in the housing of the drive mechanism, the groove may engage with at least one radially inwardly extending protrusion of the housing of the drive mechanism and/or of the drug delivery device, thereby preventing a rotational movement of the piston rod relative to the housing. Moreover, the same axially elongated groove may provide a longitudinal, hence axial guiding structure for the dose limiting member for rotatably fixing the dose limiting member to the piston rod and hence to the housing.
According to another embodiment, the dose limiting member comprises a shell-like profile, in particular a half-shell profile, extending only partially around the circumference of the piston rod. Preferably, the dose limiting member comprises a substantially even shaped inner surface, which allows the dose limiting member to glide over the threaded piston rod in axial direction. Alternative to a shell profile, the dose limiting member may also be designed as a dose limiting sleeve completely extending around the outer circumference of the piston rod. However, for the purpose of limiting relative displacement of drive sleeve and piston rod, a shell-like profile of the dose limiting member may already be sufficient. A shell-like or half-shell profiled dose limiting member may be beneficial in terms of assembly of the drive mechanism and may further provide to reduce material costs and overall weight of the drive mechanism.
According to another embodiment, the at least one stop extends in radial direction and in axial direction to engage with a correspondingly oriented stop portion of the dose limiting member. This way, a so-called radial stop can be implemented, by way of which a rotational displacement of the stop portion of the dose limiting member relative to the at least one stop can be interrupted and blocked. Moreover, since the stop and the correspondingly oriented stop portion extend in radial direction and in axial direction, respective stop faces can be provided, which when partially overlapping in axial direction, may also allow for relative axial displacement of the dose limiting member with respect to the stop.
According to another preferred embodiment, the dose limiting member comprises a distal stop portion and a proximal stop portion extending from opposite distal and proximal end sections thereof. By having a distal stop portion extending from a distal end of the dose limiting member, the drive mechanism can be effectively locked in a zero dose configuration, which is typically reached at the end of a dose dispensing procedure. The proximal stop portion which extends from the opposite proximal end section of the dose limiting member is adapted to lock the drive mechanism in a maximum dose configuration for limiting the size of a maximum single dose to be set and to be subsequently dispensed by the drive mechanism. At least one of the stop portions of the dose limiting member, preferably both stop portions, extend within tangential circumference of the dose limiting member. Preferably, the at least one stop portion does not radially protrude from the circumference of the dose limiting member.
Distal and proximal stop portions of the dose limiting member are particularly adapted to separately engage or to separately interact with respective distal and proximal stops of the drive mechanism, for limiting a rotational displacement of the drive sleeve during dose setting as well as during a subsequent dose dispensing procedure. Here, the dose limiting member provides a double function. It serves to confine and to delimit the dose setting procedure as well as the dose dispensing procedure. In particular, the distal and the proximal stop portions of the dose limiting member and their corresponding stops are arranged and oriented in such a way, that engagement of a proximal stop portion of the dose limiting member with a respective proximal stop defines a zero dose configuration, wherein the size of the dose equals zero. Moreover, the mutual engagement of the distal stop portion of the dose limiting member with a corresponding distal stop specifies and defines a maximum dose configuration or a single dose limiting configuration.
According to a further embodiment, the at least one stop is arranged at an inside wall of the drive sleeve. In this embodiment, the at least one stop preferably serves as a distal stop to engage with the distal stop portion of the dose limiting member. The distal stop of the drive sleeve preferably extends in axial and radial direction and therefore provides a stop face to engage with the correspondingly oriented distal stop portion of the dose limiting member. The at least one stop of the drive sleeve may radially inwardly protrude from the drive sleeve in order to engage with the distal stop portion of the dose limiting member. When getting in a mutual engagement configuration or in a mutual radial abutment, the drive sleeve is preferably in a zero dose configuration, i.e. at the end of a dose dispending procedure.
Generally, a radially and axially extending stop provides an accurate, well-defined and reproducable stop configuration for those components featuring such mutually engaging stop features. A radial stop generally provides a radially outwardly and/or radially inwardly extending structure provided at a particular tangential position on the inner and/or outer circumference of e.g. a tubular shaped component. In this way, a definite and well defined stop configuration can be provided which is much more precise and less sensitive to an eventual self-locking which may otherwise occur with an axial stop, such like a radially extending flange extending at a particular axial position of e.g. a last dose sleeve.
However, in alternative embodiments implementation of such axial stops is also generally conceivable, also in combination with radially acting stops.
According to a further embodiment, the at least one stop is arranged on and axially protrudes from a distal end of a clutch operably engaged with the drive sleeve. This stop provided on the clutch serves as a proximal stop to engage with the proximal stop portion of the dose limiting member. The at least one stop provided on the clutch preferably extends in distal direction from the distal end thereof. The clutch is typically located axially offset from the drive sleeve in proximal direction.
The drive sleeve is preferably subject to a rotational displacement during a dose setting procedure and may be operably engaged with the clutch. It is of particular benefit here, that its distal end and the correspondingly configured distal stop portion of the dose limiting member both comprise mutually abutting stop faces that extend in radial and axial direction.
Generally, the proximal stop typically provided on the distal end of the clutch could also be arranged at an inside wall of the drive sleeve and could extend radially inwardly from said wall to radially engage with the proximal stop portion of the dose limiting member when reaching the dose limiting or maximum dose configuration of the drive mechanism.
According to a further embodiment, the dose limiting member comprises a clicking member at a distal end having a resilient arm extending in circumferential or tangential direction. The resilient arm further comprises a latch or nose portion at a free end thereof to audibly engage with the stop, in particular with the distal stop before or when the stop portion, in particular the distal stop portion, engages with the stop. The clicking member extends in circumferential direction from the stop portion of the dose limiting member so that the clicking member reaches the stop prior to the stop portion during a rotation of the drive sleeve. The clicking member therefore advances the respective stop portion of the dose limiting member upon rotation of the drive sleeve. Preferably, the clicking member is provided at the distal end of the dose limiting member. It may therefore advance the distal stop portion of the dose limiting member.
The resilient arm of the clicking member allows for a resilient axial displacement of the clicking member when e.g. passing the distal stop provided on the inside wall of the drive sleeve. The nose or latch portion of the clicking member is designed such, that the clicking member passes the stop of the drive sleeve while the arm resiliently deforms. After the clicking member and in particular its latch portion has completely traversed the stop of the drive sleeve, the biased resilient arm will return into its initial unbiased configuration and may thus generate an audible click sound. Since the clicking member advances the motion of the trailing distal stop portion of the dose limiting member, the click sound generated by the clicking member is directly indicative that the end of a dose injection procedure approaches or that the end of the dose injection procedure has just been reached.
The clicking member is preferably provided at the distal stop portion of the dose limiting member. However, it may be correspondingly provided also at a proximal stop portion of the dose limiting member, thereby audibly indicating that the maximum dose configuration is reached or is almost reached in a dose setting procedure.
According to another preferred embodiment, the stop extends radially in or on the piston rod to engage with the dose limiting member in a last dose configuration of the drive mechanism. When interacting with the dose limiting member said stop provides a last dose limiting mechanism or an end-of-content mechanism. Since the axial position of the piston rod is unequivocally correlated to the axial position of the piston in the cartridge, the position of the piston rod is directly indicative of the filling level of the cartridge.
The stop provided in or on the piston rod typically extends in radial direction. It may extend radially inwardly, e.g. to engage with a radially inwardly extending gliding portion or tappet of the dose limiting member. It may also extend radially outwardly from the circumference or from the bottom of the groove of the piston rod. By providing a radially extending stop in or on the piston rod, axial displacement of the dose limiting member during a dose setting procedure can be appropriately limited, in such situations, where the medicament left in the cartridge is less than a dose a user is intending to set and to dispense.
Mutual engagement of the dose limiting member with the radially outwardly extending stop of the piston rod hinders the dose limiting member to be displaced further in proximal direction during a dose setting procedure. In this way and due to the mutual engagement of the dose limiting member with the piston rod and with the drive sleeve, a further rotation of the drive sleeve to increase a dose is effectively inhibited so that setting of a dose that would otherwise exceed a remaining filling level of the cartridge cannot take place.
In this embodiment, the stop extending radially in or on the piston rod serves as a last dose stop. It may but does not have to extent from a proximal end of the piston rod and may comprise a flange-like geometry.
In configurations wherein the dose limiting member slides along an axial groove of the piston rod, the last dose stop of the piston rod may be implemented in form of a proximal end of the groove. Here, the last dose stop may confine the groove in proximal direction and may provide a radially inwardly extending stop face, by means of which a proximally directed displacement of the dose limiting member can be restricted accordingly.
Hence, the last dose stop provided on or in the piston rod is adapted and designed to axially abut with a correspondingly shaped proximal stop portion of the dose limiting member.
According to this embodiment, the dose limiting member fulfils a double function. On the one hand, the dose limiting member may serve to implement a single dose limiting means, e.g. in that its proximal stop portion engages with a proximal stop arranged on a distal end of a clutch. On the other hand, the dose limiting member with its proximal stop portion may also provide a last dose limiting mechanism when the proximal stop portion engages with a last dose stop in or on the piston rod.
According to another embodiment, the drive sleeve is rotatably biased relative to the housing by means of a helical spring extending around the drive sleeve. By having arranged the dose limiting member inside the drive sleeve it does not hinder a nested arrangement of the drive sleeve in a helical spring extending there around. The helical spring is coupled with one end with the drive sleeve while another end of the helical spring is preferably coupled and connected with the housing. This way, the drive sleeve is rotatably supported for setting of a dose relative to housing against the action of the helical spring.
Such rotational and spring biasing displacement of the drive sleeve is preferably accompanied and controlled by a ratchet mechanism having at least one ratchet member to engage with a toothed surface of the housing to prevent uncontrolled and counter-directed rotation of the drive sleeve. Typically, the drive sleeve may comprise a resiliently deformable arc-shaped ratchet member extending along the outer circumference of the drive sleeve and having a ratchet tooth or nose extending radially outwardly and mating with a correspondingly shaped toothed surface provided on the inner wall of the housing. This way, the drive sleeve may be rotated in a dose setting direction in an incremented way as governed by the size of the toothed surface. Moreover, a dose incrementing dial or rotation of the drive sleeve is accompanied with an audible click-sound generated by the ratchet member meshing with the toothed surface.
Mutual engagement of the ratchet member of the drive sleeve with the toothed surface of the housing is further designed in such a way, that a user may also correct the size of a set dose, e.g. by rotating the drive sleeve in an opposite direction. However, for such a correcting and oppositely directed rotation of the drive sleeve, application of a counter-directed correction force is to be applied, which is larger than a holding force provided by the mutual engaging ratchet member and the toothed surface.
Apart from application of a counter-directed correction force above a predefined force level, other dose-correcting mechanisms are also conceivable here by means of which the ratchet mechanism may be temporally overridden.
According to a further embodiment, the piston rod is threadedly engaged with a drive nut which is axially fixed to the housing and which is rotatably supported in the housing. Preferably, drive nut and drive sleeve are co-aligned around the piston rod. The drive nut may be located distally from a distal end of the drive sleeve and it is preferably axially secured in the housing. The piston rod is typically splined to the housing or with an insert positioned in the housing and providing a radially inwardly extending flange or web with a through opening, through which the piston rod may extent axially.
It is to be mentioned here, that the insert is fixed and immobilized to the housing. The insert may be provided as a separate component to be assembled in the housing. Alternatively, insert and housing may be integrally formed. Hence, any reference made herein to the housing is equivalently valid for the housing and vice versa.
The through opening of the flange or web of the housing or of the respective insert comprises at least one radially inwardly extending protrusion that mates and engages with the at least one axially elongated groove of the piston rod. Consequently, the piston rod is rotatably fixed to the housing and is effectively hindered to rotate relative to the housing. A distally directed displacement of the piston rod relative to the housing can thus be attained by the rotating drive sleeve threadedly engaged with the piston rod.
The drive sleeve is preferably only free to rotate in one direction relative to the housing that corresponds to a dose setting procedure, during which the piston rod is driven in distal direction. Hence, the drive sleeve may be equipped with another ratchet mechanism operating in an opposite sense compared to the ratchet mechanism of the drive sleeve. The drive sleeve's ratchet mechanism only allows a dispensing-correlated rotation of the drive nut relative to the housing but prevents a counter-directed rotation. In a similar way, also the ratchet mechanism of the drive nut may comprise e.g. an arc-shaped ratchet member extending in tangential or circumferential direction at the outer circumference of the drive nut.
Also here, the ratchet member may comprise a ratchet tooth to resiliently engage with a correspondingly shaped toothed surface at an inside facing portion of the sidewall of the housing or of a corresponding insert.
For dispensing of a set dose, it is intended that the drive sleeve is axially displaceable relative to the housing for rotatably engaging the drive sleeve and the drive nut. Here, a distal end or a distal face of the drive sleeve is adapted to rotatably engage with an opposite and hence proximal face of the drive nut. Drive nut and drive sleeve therefore comprise mutually corresponding and axially extending positive locking means, such like a mutually corresponding crown wheels in order to transfer angular momentum from the drive sleeve to the drive nut during a dose dispensing procedure.
Typically, the drive sleeve is biased in axial direction relative to the housing by means of one or several spring elements. If the drive sleeve after completion of dose setting procedure is displaced against respective spring forces in distal direction, it may first rotatably engage with the drive nut and it may then consecutively disengaged from the housing. The distally directed displacement of the drive sleeve may therefore disengage the ratchet mechanism by way of which the drive sleeve is rotatably locked to the housing. Once such a release configuration is obtained, the drive sleeve is free to rotate relative to the housing under the effect of the relaxing helical spring.
Since the drive sleeve is operably and rotatably engaged with the drive nut in this release configuration the drive nut rotates accordingly, thereby advancing the piston rod in distal direction. The mutual engagement of the dose limiting member, the drive sleeve and the piston rod remains substantially unaffected by the distally directed displacement of the drive sleeve during mode switching of the drive mechanism.
Since during dose dispensing the drive sleeve rotates in a different and opposite direction compared to a dose setting procedure also the dose limiting member will travel and slide along the piston rod in the opposite, e.g. in distal direction until its distal stop portion engages with the distal stop of the drive sleeve. Since neither the dose limiting member nor the drive sleeve is threadedly engaged with the piston rod, a distally directed relative displacement of the drive sleeve and the dose limiting member relative to the piston rod during a mode switching of the drug delivery device is always possible.
According to another aspect, the invention also relates to a drug delivery device for dispensing of a dose of a medicament. The drug delivery device comprises a drive mechanism as described above and a cartridge at least partially filled with the medicament to be dispensed by the drug delivery. The cartridge is arranged in the housing of the drive mechanism or in a cartridge holder of the drug delivery device which is fixed to the housing either releasably or non-releasably, e.g. in case of a disposable drug delivery device. Consequently, the drug delivery device comprises a cartridge holder to receive and to accommodate a cartridge filled with the medicament.
The cartridge holder may be non-releasably engaged and connected to the proximal housing, e.g. by means of bonding or welding. For reusable drug delivery devices it is of particular benefit when the cartridge holder is detachable from the housing for providing access to the cartridge located therein, in particular for replacing the cartridge. A detachable connection of cartridge holder and housing can be attained by means of mutually corresponding threaded portions of cartridge holder and housing, respectively. Alternatively, it is also conceivable that cartridge holder and proximal housing of the drug delivery device are integrally formed.
Apart from that, the drug delivery device and the drive mechanism may comprise further functional components, such like an actuation member, by way of which a user may operate or manipulate the drug delivery device and its drive mechanism for setting and correcting as well as for dispensing of a correspondingly set dose.
Moreover, the drive mechanism and the drug delivery device may also comprise a dose indicating sleeve, which may rotate together with the drive sleeve and which may provide a visual indication to the user regarding the size of the dose actually set.
In the present context, the distal direction points in the direction of the dispensing and of the device, where, preferably a needle assembly is provided having a double-tipped injection needle that is to be inserted into biological tissue or into the skin of a patient for delivery of the medicament.
The proximal end or proximal direction denotes the end of the device or a component thereof, which is furthest away from the dispensing end. Typically, an actuating member is located at the proximal end of the drug delivery device, which is directly operable by a user to be rotated for setting of a dose and which is operable to be depressed in distal direction for dispensing of a dose.
The drive mechanism particularly serves to displace a piston rod in axial direction for the purpose of dispensing of a dose of a medicament. In addition, the drive mechanism typically comprises components which also form part of and have a function in at least one of the following mechanisms: a dose setting mechanism, a last dose limiting mechanism and a dose indicating mechanism. As will be apparent from the embodiments described herein various components of e.g. the drive mechanism also belong to at least one of the dose setting mechanism, the last dose limiting mechanism and/or to the dose indicating mechanism; and vice versa. Hence, the invention as described herein equally refers to and defines a drive mechanism, a dose setting mechanism, a last dose limiting mechanism and/or a dose indicating mechanism of a drug delivery device.
The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,
wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a protein, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
Exendin-4 derivatives are for example selected from the following list of compounds:    H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,    H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,    des Pro36 Exendin-4(1-39),    des Pro36 [Asp28] Exendin-4(1-39),    des Pro36 [IsoAsp28] Exendin-4(1-39),    des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),    des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),    des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),    des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),    des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),    des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or    des Pro36 [Asp28] Exendin-4(1-39),    Des Pro36 [IsoAsp28] Exendin-4(1-39),    des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),    des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),    des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),    des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),    des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),    des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;or an Exendin-4 derivative of the sequence    des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),    H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,    des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,    H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,    H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,    des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,    H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,    H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,    des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,    des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,    H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,    des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,    H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,    H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,    des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,    H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,    H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.
Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.
An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
Pharmaceutically acceptable solvates are for example hydrates.
It will be further apparent to those skilled in the pertinent art that various modifications and variations can be made to the present invention without departing from the spirit and scope of the invention. Further, it is to be noted, that any reference signs used in the appended claims are not to be construed as limiting the scope of the present invention.